rs74138760

Variant names:

• chr10-63215676-G-A
• rs74138760
• NM_032776.3:c.699C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001318153.2(JMJD1C):​c.-170C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000987 in 1,588,958 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (5 hom.)
• Consequence: JMJD1C NM_001318153.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.06
• Publications: 2 publications found

Genes affected

JMJD1C (HGNC:12313): (jumonji domain containing 1C) The protein encoded by this gene interacts with thyroid hormone receptors and contains a jumonji domain. It is a candidate histone demethylase and is thought to be a coactivator for key transcription factors. It plays a role in the DNA-damage response pathway by demethylating the mediator of DNA damage checkpoint 1 (MDC1) protein, and is required for the survival of acute myeloid leukemia. Mutations in this gene are associated with Rett syndrome and intellectual disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

JMJD1C Gene-Disease associations (from GenCC):

• 22q11.2 deletion syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Illumina
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 10-63215676-G-A is Benign according to our data. Variant chr10-63215676-G-A is described in ClinVar as Benign. ClinVar VariationId is 460276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 669 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318153.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	NM_032776.3	MANE Select	c.699C>T	p.Val233Val	synonymous	Exon 6 of 26	NP_116165.1
	JMJD1C	NM_001318153.2		c.-170C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 25	NP_001305082.1
	JMJD1C	NM_001322252.2		c.585C>T	p.Val195Val	synonymous	Exon 5 of 25	NP_001309181.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	ENST00000399262.7	TSL:5 MANE Select	c.699C>T	p.Val233Val	synonymous	Exon 6 of 26	ENSP00000382204.2
	JMJD1C	ENST00000542921.5	TSL:1	c.153C>T	p.Val51Val	synonymous	Exon 5 of 25	ENSP00000444682.1
	JMJD1C	ENST00000402544.5	TSL:1	n.671C>T		non_coding_transcript_exon	Exon 3 of 22

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 669 AN: 152114 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00116 AC: 280 AN: 241810 AF XY: 0.000892

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000206

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.000626 AC: 900 AN: 1436726 Hom.: 5 Cov.: 32 AF XY: 0.000583 AC XY: 414 AN XY: 710028

African (AFR) AF: 0.0138 AC: 452 AN: 32818

American (AMR) AF: 0.00127 AC: 55 AN: 43202

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25726

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39030

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53108

Middle Eastern (MID) AF: 0.00335 AC: 19 AN: 5674

European-Non Finnish (NFE) AF: 0.000259 AC: 283 AN: 1093272

Other (OTH) AF: 0.00145 AC: 86 AN: 59258

GnomAD4 genome AF: 0.00439 AC: 669 AN: 152232 Hom.: 3 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74426

African (AFR) AF: 0.0137 AC: 569 AN: 41546

American (AMR) AF: 0.00399 AC: 61 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00513

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Early myoclonic encephalopathy (1)
-	-	1	JMJD1C-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		3.1
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74138760; hg19: chr10-64975436; COSMIC: COSV107503941; COSMIC: COSV107503941;